Boileau Pascal, Wolfrum Christian, Shih David Q, Yang Tien-An, Wolkoff Allan W, Stoffel Markus
Laboratory of Metabolic Diseases, the Rockefeller University, New York, New York 10021, USA.
Diabetes. 2002 Dec;51 Suppl 3:S343-8. doi: 10.2337/diabetes.51.2007.s343.
Diabetes in subjects with hepatocyte nuclear factor (HNF)-1alpha gene mutations (maturity-onset diabetes of the young [MODY]-3) is characterized by impaired insulin secretion. Surprisingly, MODY3 patients exhibit hypersensitivity to the hypoglycemic actions of sulfonylurea therapy. To study the pharmacogenetic mechanism(s), we have investigated glibenclamide-induced insulin secretion, glibenclamide clearance from the blood, and glibenclamide metabolism in wild-type and Hnf-1alpha-deficient mice. We show that despite a profound defect in glucose-stimulated insulin secretion, diabetic Hnf-1alpha(-/-) mice have a robust glibenclamide-induced insulin secretory response. We demonstrate that the half-life (t(1/2)) of glibenclamide in the blood is increased in Hnf-1alpha(-/-) mice compared with wild-type littermates (3.9 +/- 1.3 vs. 1.5 +/- 1.8 min, P <or= 0.05). The clearance of glibenclamide from the blood during the first hours after intravenous administration was reduced approximately fourfold in Hnf-1alpha(-/-) mice compared with Hnf-1alpha(+/+) littermates. Glibenclamide uptake into hepatocytes was dramatically decreased in vivo and in vitro. To study the metabolism of glibenclamide in Hnf-1alpha(-/-) animals, we analyzed liver extracts from [(3)H]glibenclamide-injected animals by reverse-phase chromatography. We found that the ratio of the concentrations of glibenclamide and its metabolites was moderately increased in livers of Hnf-1alpha(-/-) mice, suggesting that hepatic glibenclamide metabolism was not impaired in animals with Hnf-1alpha deficiency. Our data demonstrate that high serum glibenclamide concentrations and an increased t(1/2) of glibenclamide in the blood of Hnf-1alpha(-/-) mice are caused by a defect in hepatic uptake of glibenclamide. This suggests that hypersensitivity to sulfonylureas in MODY3 patients may be due to impaired hepatic clearance and elevated plasma concentrations of the drug.
肝细胞细胞核因子（HNF）-1α基因突变的受试者（青年发病的成年型糖尿病[MODY]-3）中的糖尿病以胰岛素分泌受损为特征。令人惊讶的是，MODY3患者对磺脲类药物治疗的降血糖作用表现出超敏反应。为了研究药物遗传学机制，我们研究了野生型和Hnf-1α缺陷型小鼠中格列本脲诱导的胰岛素分泌、格列本脲从血液中的清除以及格列本脲的代谢。我们发现，尽管糖尿病Hnf-1α（-/-）小鼠在葡萄糖刺激的胰岛素分泌方面存在严重缺陷，但它们对格列本脲诱导的胰岛素分泌反应强烈。我们证明，与野生型同窝小鼠相比，Hnf-1α（-/-）小鼠血液中格列本脲的半衰期（t(1/2)）延长（3.9±1.3分钟对1.5±1.8分钟，P≤0.05）。与Hnf-1α（+/+）同窝小鼠相比，Hnf-1α（-/-）小鼠静脉注射后最初几小时内格列本脲从血液中的清除率降低了约四倍。格列本脲在体内和体外进入肝细胞的摄取均显著降低。为了研究Hnf-1α（-/-）动物中格列本脲的代谢，我们通过反相色谱法分析了注射[（3）H]格列本脲的动物的肝脏提取物。我们发现，Hnf-1α（-/-）小鼠肝脏中格列本脲及其代谢物的浓度比适度增加，这表明Hnf-1α缺乏的动物肝脏中格列本脲的代谢未受损。我们的数据表明，Hnf-1α（-/-）小鼠血液中高血清格列本脲浓度和格列本脲t(1/2)延长是由肝脏对格列本脲摄取缺陷引起的。这表明MODY3患者对磺脲类药物的超敏反应可能是由于肝脏清除受损和药物血浆浓度升高所致。
